| PurposeLung cancer is currently the most common malignant tumor around the world,both in incidence and death rate in my country and non-small cell lung cancer(NSCLC)accounts for the majority of lung cancer,about 85%of it.Most of these patients were diagnosed as advanced(stage ⅢB/Ⅳ).For advanced metastatic NSCLC patients who have negative driver genes without contraindications to immune checkpoint inhibitors(ICIs),first-line chemotherapy combined with immunotherapy has become the preferred treatment strategy now,but the treatment mode after drug resistance still needs to be further explored.For advanced NSCLC patients who only receive the traditional platinum-based chemotherapy in the first line,monotherapy such as docetaxel and immunotherapy has become the standard second-line treatment for NSCLC.The response rate(RR)of docetaxel was just about 10%,the median progression-free survival(mPFS)and median overall survival(mOS)were 2～4 months and 5.5～12.5months,respectively.Nivolumab was approved by the National Medical Products Administration of China on June 15,2018 for using in patients with locally advanced or metastatic NSCLC who are negative for EGFR or ALK and who have progressed after previous platinum-based chemotherapy.Although ICIs as second-line therapy showed significant improvements in RR,PFS,and OS compared with docetaxel monotherapy,with rates of 14 to 30%,2.3～4.0 months,and 9.2～13.8 months,respectively,some problems exist to be addressed,such as primary and acquired resistance,the lack of effective and prognostic bio-markers,treatment-related adverse events,the high cost and not covered by Health Care.Therefore,these restrict its wide application in domestic patients.It is still of great practical significance to analyze the changes of second-line treatment for advanced NSCLC patients in China in the past 10 years,and to study how to improve second-line treatment efficacy and survival on the basis of monotherapy.Purposes of this study:(1)To retrospectively analyze the composition and proportion of second-line treatment for advanced NSCLC patients with negative driver genes in Qilu Hospital Cancer Center,(2)This study was an retrospective analysis of the efficacy and safety of second-line treatment of advanced NSCLC with S-1 combined with non-platinum-based chemotherapy,so as to provide evidence for the optimization of second-line treatment strategies for patients with advanced NSCLC and to lay a foundation for future feasibility studies of ICIs combined with S-1 or non-platinum-based chemotherapy.Methods(1)Retrospectively analysis of the composition and proportion of second-line treatment for patients with advanced NSCLC patients admitted to Qilu Hospital Cancer Center from January 2011 to December 2020.Inclusion criteria included staging IIIB/IV lung cancer by the International Association for the Study of Lung Cancer(IASLC)7th Edition of TNM Staging with inoperable or non-definitive chemoradiotherapy;the pathological types were NSCLC,squamous carcinoma or non-squamous carcinoma;negative EGFR/ALK or unknown;previously treated with platinum-based chemotherapy.Exclusion criteria included mixed small-cell or large-cell neuroendocrine carcinoma;positive EGFR/ALK;complicated with other malignant tumors.Second-line treatment regimens were collected and classified as monotherapy,platinum-based chemotherapy,non-platinum dual-drug chemotherapy(excluding S-I);S-1 combined with non-platinum-based chemotherapy,monotherapy combined with antiangiogenic therapy,dual drug chemotherapy combined with antiangiogenic therapy;immunotherapy;immunotherapy combined with antiangiogenic therapy.According to the start date of this study and the time of approval of Nivolumab by the National Medical Products Administration of C hina,second-line treatment regimens over 10 years were divided into the first phase(January 2011-December 2014),the second stage(January 2015-June 2018)and the third stage(on June 6,2018-December 2020).(2)The analysis of the efficacy and safety of second-line treatment of advanced NSCLC with S-1 combined with non-platinum-based chemotherapy:This study retrospectively analyzed advanced NSCLC patients receiving this chemotherapy from 2015.1to2020.5 in Qilu Hospital,Qingdao branch of Qilu Hospital,Shandong Cancer Hospital,The First People’s Hospital of Zibo,The People’s Hospital of Zhangqiu,Linyi People’s Hospital and Jinan Fourth People’s Hospital.The inclusion criteria included NSCLC;staging ⅢB/Ⅳ lung cancer according to the IASLC 7th Edition of TNM Staging with inoperable or non-definitive chemoradiotherapy;and age≥18 years,≤75 years,Eastern Cooperative Oncology Group performance status ≤1;negative EGFR/ALK or unknown,or patients with positive driver genes and resistant to targeted therapy(TKI);and previously only treated with platinum-based chemotherapy;according to RECIST of solid tumor:there should be at least one measurable target lesion that can accurately measure the maximum diameter and the maximum diameter of the lesion should be≥10mm.Exclusion criteria is symptomatic brain metastasis.The cutoff date for survival follow-up was October 3 1,2020.The study chemotherapy regimens were Docetaxel combined with S-1 or Gemcitabine combined with S-1.The dose range was:S-1:40-60mg,bid;Docetaxel:60-75mg/m2,d1;Gemcitabine:1000mg/m2,d1,d8.The primary endpoint is PFS.Secondary endpoints were RR,OS and safety.Statistical analysis:The demographics and disease characteristics of patients were analyzed by descriptive statistics.The measurement data of normal distribution was expressed as mean±standard deviation,the measurement data of skewed distribution was expressed as median(interquartile range),and the count data was expressed as number(%).Survival curves were estimated using the Kaplan-Meier method and Log-rank test.The 95%confidence interval was estimated using the log-log method.COX regression analysis was used for multivariate analysis and regression method was used to screen risk factors.All statistical analyses were carried out using R 3.5.0 and SAS 9.4 software,and perform two-sided test(α=0.05).The response rate of Docetaxel was set as 10%in historical control.Fisher’s exact probability method was used to compare with historical control.p<0.025 in unilateral test was considered statistically significant.Matching-adjusted indirect comparisons were used to compare the efficacy of S-1 in combination with non-platinum-based chemotherapy and Docetaxel in a weighted balanced population.Safety analysis was estimated according to the CTCAE standard.The subsequent treatment information was available by telephone or medical records.Results(1)The composition and proportion of second-line treatment for patients with advanced NSCLC patients admitted to Qilu Hospital Cancer Center:452 patients were enrolled,among which 228 patients(50.44%)received the platinum-based chemotherapy,which was the most commonly used second-line treatment.The proportion of patients receiving single drug chemotherapy showed a decreasing trend in three stages,which were 18.13%,7.74%,5.64%,respectively.The proportion of platinum-based chemotherapy also showed a decreasing trend,which were 75.63%,42.86%,28.23%,respectively.The proportion of S-1 combined with non-platinum chemotherapy were 1.25%,42.86%,16.93%,respectively,with the highest acceptance rate in the second stage.The proportion of combined antiangiogenic therapy increased in three stages,which were 3.12%,6.54%,3 7.10%,while the proportion of immunotherapy reached 12.10%in the third stage.(2)This study enrolled in 87 patients of security analysis,83 patients of survival analysis and 76 patients of progression-free survival analysis.The m.PFS was 5.23 months[95%confidence interval(CI)4.40-7.90 months],the mOS was 14.40months(95%CI:12.53-17.40 months),RR was 22.89%,compared with 10%for the historical control(p<0.001).The PFS and OS of this study indirectly adjusted by matching weighting was compared with those of docetaxel.The weighted mPFS(7.90 months)and mOS(19.37 months)of S-1 combined with non-platinum-based chemotherapy were significantly higher than those of the historical control study.(3)Univariate and multivariate Cox regression analysis of PFS and OS:Univariate analysis showed that no correlation was observed between age,sex,ECOG score,smoking,TNM stage,histological type,brain metastasis or not and PFS.Patients whose PFS>9m in first-line,compared with patients whose PFS≤9m,showed a tendency of prolongation in PFS(p=0.058).The OS was closely related to the short-term efficacy of second-line chemotherapy(p<0.001),but not related to other factors.Multivariate Cox analysis also showed that PFS of this study was closely correlated with PFS of first-line chemotherapy(p=0.049),and OS was closely correlated with RR of second-line chemotherapy(p<0.001)(4)The incidence of adverse events in this study was 88.51%,and the incidence of grade 3-4 adverse events was 20.69%.The most common adverse drug reactions of were anemia(60.92%),nausea(55.17%)and leukocytopenia(33.33%),and the most common grade 3/4 severe adverse drug reactions were neutropenia(14.94%).The dose reduction rate was 11.49%,and the treatment discontinuation rate was 4.60%.(5)Among the 77 patients who were followed up subsequent treatment,63 patients(81.82%)received subsequent systematic treatment,of which chemotherapy accounted for 32.47%.Antiangiogenic therapy accounted for 28.57%as monotherapy or in combination.6.49%of patients received PD-1 immunotherapy.Conclusion(1)From 2011 to 2020,the commonly used second-line chemotherapy for advanced NSCLC were,in order,platinum-based chemotherapy,S-l combined with non-platinum-based chemotherapy,antiangiogenic therapy combined with chemotherapy,monotherapy,immunotherapy(PD-l monoclonal antibody),etc.The platinum-based chemotherapy and monotherapy showed a decreasing trend over time,and the prescription rate of S-1 combined with non-platinum-based chemotherapy was the highest from 2015 to 2018.The proportion of combined antiangiogenic therapy and immunotherapy showed a rapidly increasing trend from 2018 to 2020.(2)Compared with docetaxel monotherapy as the standard second-line,the response rate was significantly increased,the progression-free survival and overall survival were significantly longer than those of the historical control,and the adverse reactions were tolerable,confirming the safety and efficacy of the combination of S-1 and non-platinum-based chemotherapy as second-line treatment for advanced NSCLC,and also lays a good foundation for feasibility studies of S-1 combined with ICIs or antiangiogenic therapies. |
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